WOSCOPS

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Shepherd J, et al. "Prevention of Coronary Heart Disease with Pravastatin in Men with Hypercholesterolemia". The New England Journal of Medicine. 1995. 333(20):1301-1308.
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Clinical Question

In men with hyperlipidemia, what is the benefit of pravastatin in reducing CV events?

Bottom Line

Among men with hyperlipidemia, pravastatin reduced the composite endpoint of nonfatal MI or death from CAD at 5 years.

Major Points

The West of Scotland Coronary Prevention Study (WOSCOPS) was the first trial to demonstrate a significant reduction in CV events with statin therapy for primary prevention. WOSCOPS randomized 6595 middle-aged men with hyperlipidemia and no previous history of MI to pravastatin or placebo. This trial demonstrated a 31% relative risk reduction of coronary events, an effect that was seen within 6 months of randomization. The absolute benefit was 2.4%; therefore, the number needed to treat was 33 patients in order to prevent one coronary event at 5 years.

In addition, it can be estimated that treating 1000 middle-aged men with hyperlipidemia and no evidence of previous MI with pravastatin for 5 years will result in 14 fewer coronary angiograms, 8 fewer revascularization procedures, 19 fewer nonfatal MIs, 7 fewer CV deaths, and 9 fewer overall deaths.

Guidelines

ACC/AHA Cholesterol treatment to reduce ASCVD risk (2013, adapted)[1]

  • Statins for primary prevention in non-diabetics:
    • No targets for specific LDL or HDL cholesterol levels
    • If age ≥21 and LDL-C ≥190 mg/dL, start high-intensity therapy (class I, level B, NHLBI grade B)
      • If not tolerating high-intensity therapy, use maximum tolerated dose
    • In adults age 40-75 with LDL-C 70-189 mg/dL, use Pooled Cohort Equation to estimate 10 year ASCVD risk individuals (class I, level B, NHLBI grade E):
      • If ASCVD risk ≥7.5%, start moderate or high intensity statin therapy (class I, level B, NHLBI grade A)
      • If ASCVD risk 5 to <7.5%, it is reasonable to offer moderate intensity statin therapy (Class IIa, level B, NHLBI grade C)

Design

  • Multicenter, double-blind, parallel-group, randomized, placebo-controlled trial
  • N=6,595 men with hyperlipidemia
    • Pravastatin (n=3,302)
    • Placebo (n=3,293)
  • Primary outcome: Composite endpoint of nonfatal MI or death from CAD
  • Setting: Scotland
  • Enrollment: February 1989 to May 1995
  • Mean follow-up: 5 years
  • Analysis: Intention-to-treat

Population

Inclusion Criteria

  • Males aged 45-64 years
  • Total cholesterol ≥252 mg/dL on initial screening
  • LDL cholesterol
    1. LDL ≥155 mg/dL at visits 2 and 3
    2. LDL ≥174 but ≤232 mg/dL at one or both of screening visits 2 and 3

Exclusion Criteria

  • History of treated MI
  • Hospitalization for angina within prior 12 months
  • EKG abnormalities, arrhythmia, frequent PVCs, ≥2nd degree AVB
  • SBP >180 or DBP >110 with treatment
  • History of rheumatic heart disease
  • Congenital heart disease
  • Cor pulmonale, chronic bronchitis, emphysema, or kyphoscoliosis associated with EKG changes
  • Cardiomegaly, congestive cardiac failure, or significant valvular heart disease
  • Other suspected serious physical illness
  • Psychiatric illness
  • Current lipid-lowering therapy
  • Laboratory exclusions

Baseline Characteristics

  • Mean age: 55 years
  • BMI: 26 kg/m2
  • Mean BP: 136/84
  • Angina: 5%
  • Intermittent claudication: 3%
  • DM: 1%
  • HTN: 16%
  • Smoking status:
    • Never smoker: 22%
    • Former smoker: 34%
    • Current smoker: 44%
  • Total cholesterol: 272 mg/dL
  • LDL: 192 mg/dL
  • HDL: 44 mg/dL
  • Triglycerides: 163 mg/dL
  • Minor EKG abnormality: 8%

Interventions

  • 160,000 males were invited to attend the clinics to assess their coronary risk factors
  • 81,161 returned for 1st visit. If nonfasting total cholesterol ≥252 mg/dL but no history of MI, patient given lipid-lowering dietary advice and asked to return 4 weeks later
  • 20,914 returned for 2nd visit. If fasting LDL ≥155/dL, patient advised to stay on lipid-lowering diet for further 4 weeks and then to return for third visit
  • 13,654 returned for 3rd visit. A second fasting lipid panel and 12-lead EKG were obtained
  • 6,595 males were ultimately randomized to pravastatin 40mg PO daily or placebo
    • Dietary advice reinforced every 3 months
    • Fasting lipid profile obtained every 6 months
    • Full medical examination and EKG recorded annually

Outcomes

Comparisons are pravastatin vs. placebo. Endpoints expressed as absolute risk at 5 years.

Primary Outcomes

Nonfatal MI or death from CAD
5.5% vs. 7.9% (RR 0.69; 95% CI 0.57-0.83; P<0.001)

Secondary Outcomes

Nonfatal MI
4.6% vs. 6.5% (RR 0.69; 95% CI 0.55-0.85; P<0.001)
Definite coronary events
1.2% vs. 1.7% (RR 0.72; 95% CI 0.48-1.10; P=0.13)
Definite plus suspected coronary events
1.3% vs. 1.9% (RR 0.67; 95% CI 0.46-0.99; P=0.042)
CV mortality
1.6% vs. 2.3% (RR 0.68; 95% CI 0.57-0.97; P=0.033)
All-cause mortality
3.2% vs. 4.1% (RR 0.78; 95% CI 0.60-1.00; P=0.051)
Frequency of coronary angiography
2.8% vs. 4.2% (RR 0.69; 95% CI 0.53-0.90; P=0.007)
PTCA or CABG
1.7% vs. 2.5% (RR 0.63; 95% CI 0.44-0.89; P=0.009)

Change in lipid levels with pravastatin

  • Total cholesterol: 20% decrease
  • LDL: 26% decrease
  • HDL: 5% increase
  • Triglycerides: 12% decrease

Subgroup Analysis

  • The beneficial effects of pravastatin therapy were evident in all subgroups, including age (<55 or ≥55 years), smoking status (smoker or nonsmoker), and LDL (<189 or ≥189 mg/dL).
  • The benefit was independent of other predictors of outcome including diabetes, nitrate consumption, EKG abnormalities, BP, family history of CAD, and angina pectoris.

Adverse Events

No difference was observed in the occurrence of myalgia, muscle aches, elevated creatinine kinase, or elevated aspartate aminotransferase and alanine aminotransferase.

Funding

Supported by a research grant from the Bristol-Myers Squibb Pharmaceutical Research Institute.
  1. Stone NJ, et al. "2013 ACC/AHA guideline on the treatment of blood cholesterol o reduce atherosclerotic cadiovascular risk in adults." Journal of the Amercan College of Cardiology. 2014;63(25 Pt B):2889-2934.